Branced polyoxaalkyl macromolecules

ABSTRACT

Branched, dendrimeric-type macromolecules composed essentially of a central nucleus and of a series of polyoxaalkyl chains that depart from said nucleus and spread into the surrounding space branching in a cascade fashion useful as carriers of drugs, contrast agents, etc.

The present invention concerns a new class of branched, dendrimeric-typemacromolecules composed essentially of a central nucleus and of a seriesof polyoxaalkyl chains that depart from said nucleus and spread into thesurrounding space branching in a cascade fashion until the desired sizeis obtained. The molecules formed in this way do not have excessivefunctional crowding on their outer surfaces. The invention also includesthe synthetic method for obtaining these molecules as well as theiruses.

Over the past decade dendrimeric macromolecules have stirredconsiderable interest because of their intrinsic features which are verydifferent from those of highly polydispersed linear or branched polymersproduced by polymerisation processes. On the contrary, dendrimers areobtained through synthetic procedures involving a step-by-step growthwhich allow for greater control over molecular mass, size and shape.Dendrimeric molecules are characterized by having a central nucleus,termed "core", from which chains originate and branch off to theperiphery to occupy all the available space. This leads to amultibranched ordered structure having many functional groups on theexternal surface. Such a molecule can have a highly congested surfacecapable of controlling the diffusion of small chemical entities into andout of the dendrimeric structure. Depending on the kind and dimension oftheir constituents, such macromolecules can assume different geometricshapes (spheroidal, cylindrical, mushroom-like, ellipsoidal etc.).Compared with other branched polymers, these macromolecules usually areendowed with a relatively low intrinsic viscosity (limiting viscositynumber) even at high molecular masses.

Macromolecules with different denominations, synthesized and patented bydifferent research groups can be included in this class of derivatives.The main classes are shown in Table I.

                                      TABLE I                                     __________________________________________________________________________    Main classes of dendrimeric macromolecules                                    Denomination                                                                          Research group                                                                       References                                                                          Main patents                                                                         Chemical structures                               __________________________________________________________________________    Starburst                                                                             Tomalia                                                                              1-5   US 4,587,329                                                                         Starburst dendrimers include:                                                 polyamidoamines (PAMAM),                                                      polyethyleneimines (PEI),                                                     polyethers (PE) polythioethers.                   Denkewalter                                                                           Denkewalter                                                                          6     US 4,289,872                                                                         Lysine-based branched polymers.                   dendrimers                                                                    Arborols                                                                              Newkome                                                                              7-12  WO 9321144                                                                           Arborols include molecules having                                29           either a benzene "core" or a                                                  "core" with four saturated                                                    hydrocarbon branches.                             Dendrimeric                                                                           Frechet                                                                              13-19 US 5,041,516                                                                         Functionalized benzenes poliethers                poliethers           WO 9208749                                                                           synthesized through an original                                        WO 9321259                                                                           synthetic approach (convergent                                                synthesis).                                       DSM dendrimers                                                                        De Brabander-                                                                        30    WO 9314147                                                                           Poly(propylene imine) dendrimers                          van den Berg        with branches prepared from vinyl                                             cyanide units.                                    __________________________________________________________________________

Starburst Dendrimers (Ref. 1-5)

Starburst dendrimers synthesized by Tomalia et al. include:

a) Starburst polyamidoamine (PAMAM) dendrimers (Ref. 1-3)

These are compounds with either a nucleophilic or an electrophilic"core". One of the most widely used nucleophilic "core" is ammonia. Inthis case, the synthesis involves a preliminary reaction with methylacrylate (Michael's addition) to form a triester which is then amidatedwith ethylenediamine to form a first generation molecule containing 3terminal amino groups (Scheme 1). ##STR1## By repeating these syntheticsteps the dendrimer grows in diameter by approximately 10 Å pergeneration evolving from an undefined shape for generations 0-2 to anoblate spheroid for generations 3-4 and finally to a nearly symmetricalspheroid for generations 5 and higher. Another example of "core" isethylenediamine.

b. Starburst polyethyleneimine PEI) dendrimers (Ref. 1)

These molecules derive from a symmetrical "core" comprising 3 aminofunctions, obtained through alkylation of diethylenetriamine withaziridine. The first generation is obtained by reacting this "core" withN-tosylaziridine or N-mesylaziridine and by subsequent deprotection(Scheme 2). ##STR2##

x=tosyl or mesyl

The higher generations are obtained by repeating these synthetic steps.PEIs differ from PAMAMs because of their short branch-segment lengths.For each generation, the diameter increases by only 5 Å compared withthe 10 Å of PAMAMs. The CPK® (Corey Pauling Koltun) models indicate thatthese dendrimers are much more compact and congested than the starburstPAMAMs. These models show that the 5th generation is impossible due tothe so-called "dense-packing" phenomenon or excessive crowding ofsurface functional groups, phenomenon which makes impossible or onlypartially possible the further growth of the molecule (Ref. 1). Comparedwith PAMAMs, PEIs possess more stable chemical bonds.

c) Starburst polyether dendrimers (Ref. 1, 4, 5)

These dendrimers are examples of macromolecules endowed with the maximumpacking effect due to the high multiplicity of the "core" (4 functionalgroups), and of the branching points (3 functional groups per unit).This gives rise to very compact molecules having highly congestedmicrodomains which possess only very small internal voids. The startingcompound, pentaerythritol tetrabromide, is reacted with pentaerythritolmolecules in which the 3 hydroxyl functions are protected asorthoesters. The resulting molecule assumes a spheroidal shape from thefirst generation. As a consequence by the fourth generation, whichshould possess 324 hydroxy groups on the external surface, a highlyconstrained and rigid system with no internal voids or channels shouldbe formed. Indeed, the fourth generation cannot itself be obtainedbecause of excessive steric hindrance on the external surface. Syntheticstudies revealed that branching defects became progressively higher asone advanced from generation 2 to generation 3.

d) Starburst polythioether dendrimers (Ref. 1)

These are similar to the polyethers except that a mercaptobicyclicorthoester is used for the coupling step instead of the hydroxybicyclicorthoester. In this way, a dendrimer containing thioether bonds andhydroxyl groups on the external surface is obtained. In the case ofpolythloether dendrimers, the molecules are already hindered by thesecond generation and attempts to obtain the third generation have sofar been unsuccessful. The main difference between PAMAMs and polyetherand polythioether dendrimers is that the latter molecules assume acongested structure starting already from the first generation and havealmost no internal voids. They are therefore much more compactmolecules.

Denkewalter's dendrimers (Ref. 6)

Denkewalter et al. (Ref. 6) reported the synthesis of lysine-baseddendrimers obtained by using the classic approach for solid-phasepeptide synthesis. The lysine trees were constructed using abenzhydrylamine resin and N-protected tert-butyloxycarbonyl lysine. Thebranching points, i.e. the lysine amino groups, are located on segmentsof different length.

Polyamidoalcohol dendrimers (arborols) (Ref. 7-12, 29)

They have been synthesized by Newkome and co-workers. This class ofdendrimers is an example of a heterogeneous series of highly branchedcompounds with a large number of functional groups on the externalsurface. In the literature, only low-generation molecules are described,usually of just first or second generation. The cascadepolymers havebeen synthesized starting either from a benzene ring, to which threecascade spheres are attached, or from alkyl halides with a singlecascade sphere. More recently, arborols with a skeleton consisting ofsaturated hydrocarbon chains with external hydrophilic groups, have beendeveloped. These macromolecules can host non-polar molecules in theirlipophilic cavities and may thus be regarded as unimolecular micelles.

Polyether dendrimers (Ref. 13-19)

These derivatives have been synthesized by Frechet and co-workersthrough an original synthetic approach involving two distinct steps:

a) preparing preformed dendrimeric fragments containing a reactivegroup, termed the "focal point";

b) assembling the dendrimeric molecule through reaction of the fragmentfocal points with the "core", which consists of a polyfunctionalmolecule.

However, by this approach the synthesis of dendrimers of fourth andhigher generations is difficult because the reactivity of the focalpoint is reduced due to steric hindrance. The propagation monomers ofthese molecules are constituted by polyfunctional benzenes and thusthese molecules are endowed with a certain degree of rigidity.

The first attempts at synthesizing branched molecules date back to 1978when Buhleier, Wehner, and Vogtle, (Ref. 20) proposed a synthetic schemethat involved the frequent repetition of similar steps which would addsuccessive branches to a starting molecule. In this way, compounds withincreasingly growing cavity size were obtained. This process, termed"cascade-like" synthesis, used linear or cyclic mono or diamines asstarting molecules which, by reaction with acrylonltrile followed byreduction, give rise to new branching points. Recently, other types ofdendrimers have been synthesized. Miller et al. (Ref. 21) prepared aseries of dendrimers, containing 4, 10, 22 or 46 benzene rings whichpossess symmetrical and rigid molecular structures. Such dendrimers arethermally stable and, with the exception of the sparingly soluble firstgeneration, are soluble in organic solvents such as THF, toluene andchloroform. The author suggested the use of these products as standardsfor size-exclusion chromatography. Uchida et al. (Ref. 22) and Mathiasand Carothers (Ref. 23) synthesized silicone-based dendrimers up to thethird generation. However, for the dendrimers of Mathias and Carothers,the absolute molecular weight, molecular weight distribution anduniformity of branching are still unknown.

Dendrimers having charges within the cascade structure have beendescribed by Rengan and Engel (Ref 24, 25). These are phosphonium orammonium sites and only the first three generations have beensynthesized. Morikawa et al. (Ref. 26) synthesized starburst dendrimerscontaining polysiloxane units up to the third generation whose potentialapplications could be as drug carriers. Nagasaki et al. (Ref. 27)described the synthesis of arborols with encapsulated crown ethers inthe hope of producing compounds with novel physical properties such asthe selectivity towards alkali metal ions, the allosteric effect in themetal-binding process, the conformational change induced by themetal-binding and the polyelectrolyte-like behaviour of the resultingmetal complexes. However, none of these characteristics have so far beendemonstrated. These dendrimers were synthesized by the convergentsynthetic approach. Because of the insolubility of the first generationand the steric hindrance of functional groups on the molecule, thedivergent approach was also examined but failed to give the desiredmolecules.

To date only the second generation has been obtained.

Polynuclear transition metal complexes of dendrimeric nature have beensynthesized by Serroni et al. (Ref. 28).

Building repetition blocks are linked not only through covalent bondsbut also through metal chelate bonds.

Brabander-van den Berg et al. (Ref. 30) synthesized poly(propyleneimine) dendrimers up to the fifth generation. These dendrimers areobtained through repetitive double Michael addition of acrylonitrile toprimary amines, followed by a heterogeneously catalyzed hydrogenation ofthe nitrites. These kinds of dendrimers are not sensitive to hydrolyticdegradation and are stable at high temperature. The process by whichthey are prepared is suitable for large scale productions.

As already mentioned, dendrimers reported in the literature have beenobtained by two different synthetic approaches:

a) divergent synthesis; b) convergent synthesis.

The syntheses of most dendrimers have been accomplished using thedivergent process. This implies that a polyfunctional molecule is usedas a "core" and that, in order to introduce multiplicity, eachfunctional group is bonded to a molecule which also comprises more thanone protected reactive site ("propagation monomer"). A first generationdendrimer is thus formed which, by exhaustive addition ofpolyfunctionalized monomers, gives rise to the next generation and soon. Monomer protection/deprotection systems need to be used in order toperform the selective modification of specific groups at each syntheticstep.

Convergent synthesis, as first proposed by Frechet, differs from thedivergent approach in that growth starts at what will become theperiphery of the macromolecule.

Such a method results in the formation of large dendrimeric fragments,which ultimately are attached through a reactive group ("focal point")to a polyfunctional "core".

Convergent synthesis has certain advantages over divergent synthesis.With divergent synthesis, the molecule's growth occurs through thesimultaneous addition of an increasing number of reactive sites. Withthe convergent approach, on the other hand, size increase involves alimited number of reactive sites. Convergent synthesis makes use of asmaller excess of reagents. Possible side reactions are thereforeavoided and the final products more easily purified.

However, one limitation of the convergent approach is that, as the sizeof the dendrimers increases, there is an increase in the sterichindrance near the functional group, or focal point, which prevents thegroup from reacting with the "core". This limitation is also common indivergent synthesis since the size of the molecule increases more slowlythan the number of external functional groups. This leads to an increasein steric hindrance around the functional groups which are thusprevented from reacting to give the next generation.

There are notable differences among the different types of dendrimers.With regard to the starburst dendrimers, PAMAM and the polyetherspossess different multiplicity of the "core" (3 for PAMAM; 4 for thepolyethers); as a result PAMAM are much less sterically hindered thanthe polyethers and show internal cavities. These characteristics allowthe synthesis of PAMAM products with higher generation numbers than ispossible with polyethers for which the phenomenon of "dense-packing" isalready apparent by the third generation. On the other hand, the earlygenerations of PAMAM dendrimers, unlike the polyethers, do not havedefinite shapes; only the more advanced generations of PAMAM dendrimershave definite shapes. In addition, the large excess of reagents(typically ethylenediamine) that are required for the synthesis of PAMAMcan cause problems.

In the early generations these reagents are easily removed.

However, as dendrimers grow, the removal of these excesses becomes moredifficult. The same is true for certain by-products which may arise fromincomplete Michael addition reactions, from intramolecular cyclizations,from fragmentation due to retro-Michael reactions or from intermolecularcyclizations that result in the formation of bridges between twodendrimers. These problems are not seen with starburst polyethers wherean excess of reagents is not necessary and where the dendrimers arecrystalline.

This makes the purification of polyether dendrimers much easier.

As regards L-lysine-based Denkewalter dendrimers, they have asymmetric"branches" and their structures have not been rigourously established.The different lengths of the "branches" can cause steric hindrancebecause a few functional groups are buried in the internal part of themolecule and therefore sterically hindered and unreactive.

Newkome et al. (Ref. 8-12, 29) have synthesized less branched, lesssterically hindered molecules which have large lipophilic internalcavities capable of accepting hydrophobic molecules and which insolution behave similarly to micelles. The synthesis of such moleculesis rather complex, because of the unreactivity of the neopentyl centre("core") to nucleophilic reactions (Ref. 11). To overcome this drawback,the introduction of a "spacer" of at least 3 atoms was necessary.

The dendrimeric macromolecules described above have been synthesizedwith specific uses in mind. They could, for example, be used astransporters of high quantities of substances and it is for this reasonthat dendrimers are extensively studied as possible "carriers" for thecontrolled and targeted release of drugs. It is possible to preparedendrimers with a lipophilic interior and a hydrophilic surface thusobtaining molecules that can function as micelles. Compared to micelles,such molecules, as a result of their intrinsic characteristics, couldshow much greater stability. By utilizing suitable monomers in thelatter generation, it is theoretically possible to control the porosityof the external sphere of the molecule. In this regard, dendrimers canperhaps be compared with cells. Furthermore, these polymers arecharacterized by large surface areas which, in combination with highsolubility in organic solvents, might facilitate their use as carriersof catalysts that could be recovered at the end of the reaction bysimple extraction or filtration.

Compounds that are suitable for association with dendrimers are, ingeneral, molecules that can be used either for therapeutic treatment orfor in vivo or in vitro diagnosis. Compounds of this type are forexample pharmaceuticals (such as antibiotics, analgesic,antihypertensives, and cardiotonics) used in the treatment of variousdiseases; radionuclides; signal generators and absorbers; antibodies;metal chelates; opacifying diagnostics and hormones. The in vivo and invitro diagnostic procedures which could benefit from the use ofdendrimer derivatives are, for example: radioimmunologic assays,electron microscopy, ELISA, X-ray imaging, magnetic resonance imaging(MRI) and immunoscintigraphy. Dendrimers can also have other uses, forexample as "carriers" of chemical substances for agriculture, asadhesives, as absorbents, as oil/water demulsifiers, as thickeners ofplastic materials, as calibration standards for ultrafiltrationmembranes and electron microscopy, as standards for size-exclusionchromatography, and as agents to modify the Theological properties ofsolutions of dyes and paints. Despite all these possible applications,however, none as yet have been fully realised. This is in part due tothe difficulties in synthesizing dendrimers with a large number ofgenerations (because of the "dense-packing" problem), and in partbecause of the difficulties in the synthesis of three-dimensionalstructures with adequate internal cavities, in terms of number anddimension, for the intended use.

The objects of the present invention are new, dendrimeric-typemacromolecules that comprise the following structural groups:

a) a central "core", derived from a polyvalent organic molecule fromwhich at least two polyoxaalkyl chains originate,

b) at least two polyoxaalkyl chains, preferably polyoxyethylene orpolyoxypropylene, that are connected to the above-mentioned "core",

c) at least two polyvalent branched organic residues attached to theends of said chains which function as branching points for thesubsequent growth of the molecule, because each of these points can bereacted with two or more reactive groups of other polyoxaalkyl chains,

d) possibly further polyoxaalkyl chains and branching points added insuccession until the molecule reaches the desired dimension.

One polyoxaalkyl chain, taken together with its branching point,constitutes a growth, or repetition unit. The total amount of growthunits comprised in the same shell or growth level represents ageneration.

"Core" and branching points are characterized by a multiplicity numberwhich refers to either the number of functional groups on the "core",that enable growth of the molecule, or to the degree of branchingpossible at each branching point.

The introduction of the first branching point in the molecule determinesthe first generation, the introduction of a successive branching pointdetermines the second generation and so on. The length of thepolyoxaalkyl chain between the "core" and the first branching point, orbetween one branching point and the next one, can vary.

Such chain lengths are chosen according to the structure and thecharacteristics required for the macromolecule. For example, the chainlength influences the formation of the internal cavities within thestructure and/or the compactness (density) of the molecule, and in theearly generations particularly, its geometric form as well. Thepolyoxyethylene chains, as a non-limiting example of polyoxaalkylchains, are characterized by the -- OCH₂ CH₂ !n-- unit where n is anumber from 0 to 25 and preferably from 0 to 15. It is thereforepossible, when n=0, to have two branching points next to each otherwithout a polyoxaalkyl chain separating them. Nevertheless, highlypreferred compounds are those in which at least one of the generationsinclude polyoxaalkyl chains in which n is different from 0. The distancebetween the "core" and the first branching point, or between onebranching point and next one, is determined by the length of thepolyoxaalkyl chain, i.e. by the value of n. This value can be equal ineach generations or can vary from generation to generation.

The central nucleus of the compounds of the present invention can bederive from any polyvalent, aliphatic organic open chain residue, bothbranched and not, or from alicyclic residues, or from heterocyclicresidues containing N, O and/or S, or from aromatic or heteroaromaticresidues. All of them are substituted by at least two reactive groups towhich the polyoxaalkyl chains of the first generation are covalentlyattached. The "core" can also possess one or more reactive groups thatdo not participate to the growth of the molecule but which are possiblyavailable for the coupling to other structures or as dimerizationpoints. Non-limiting examples of "core" include, among others, NH3,substituted amines, diamines, suitably functionalized aromatic rings,molecules with neopentyl centres (pentaerythritol,hydroxymethylpropantriol), and triaza- and tetraazamacrocycles.Branching points can consist of polyvalent residues with at least two orthree reactive functions suitable for introducing multiplicity. In eachdendrimer, the branching points can be the same in each generation ormay vary from generation to generation.

Multiplicity can also be introduced for example using polyoxaalkylchains in which the terminal part is already branched. The multiplicityof the "core", the multiplicity of the branching points and the value ofn can be chosen according to the characteristics/properties desired inthe final macromolecule. In this way it is possible to obtainmacromolecules with different distributions of functional groups on theexternal surface: for example, zonal distribution if the polyoxaalkylchains connected to the "core" are long and those of the branches short,or uniform distribution if the polyoxaalkyl chains are of equal length.In both cases there will be a different density of terminal groupsand/or chains between the peripheral and the central part of themolecule. Increasing the branching multiplicity, with all otherparameters equal, results in a notable increase of hindrance at theperipheral part of the structure, relative to the central part. With thedegrees of freedom conferred by the length of the polyoxaalkyl chains,by the multiplicity of the "core" and the branching points, one canobtain macromolecules with internal cavities of different dimensions,which are either all equal or which vary from generation to generation.

A further advantage arising from the introduction of polyoxaalkyl chainsbetween the "core" and the first branching point, or between onebranching point and the next one, is that in this way it is possible toconstruct molecules that are able to grow further giving structures witha large number of generations. This is the fundamental point of thepresent invention. Additionally, it is also possible to avoid thephenomenon of "dense-packing", a phenomenon that severely hampers thepreparation of the dendrimers of the prior-art by restricting the numberof successive generations obtainable. As a general rule, one of the mainobstacles to the synthesis of dendrimeric structures is the excessivesurface area crowding that inevitably arises with higher numbers ofgenerations. For this reason the growth of the structure becomesprogressively more difficult; for example, preparation of molecules ofthe third generation, in the case of polythioethers, or of the fourth inthe case of polyethers, is effectively impossible as reported by Tomalia(Ref. 1).

On the contrary the introduction of polyoxaalkyl chains enables thepreparation of molecules with less compact structures. For thesemacromolecules, problems due to the inclusion of reagents and solventsduring the various synthetic steps, phenomenon which can causesignificant difficulty during the purification process, are very muchreduced.

The external surfaces of the macromolecules of the present invention arewell provided with functional groups such as for example hydroxyl,tosyl, mesyl, tresyl, brosyl and similar groups,trifluoromethanesulfonyl, phthalimido, amino, thiol, aldehydo, nitrilo,acetyl, pyranyl, cyclic orthoester, carboxyl and amido groups.

As a consequence, the compounds of the present invention may be ideallysuited to the transport of drugs and/or molecules for use in diagnosticimaging. Both these classes of compounds can be linked to suchmacromolecules, either directly or through suitable spacer chains,alternatively they can be included in the macromolecules themselves.

Concerning diagnostic imaging, it is, for example, possible to obtaincontrast agents for magnetic resonance (MRI) by linking paramagneticmetal chelates, such as chelates of polyaminopolycarboxylic acids, tothese molecules. In this respect they could represent a good solution tothe development of new effective blood-pool agents.

Ferromagnetic or superparamagnetic (ferrite, magnetites or derivativesthereof) compounds can also be included in the internal cavities of themacromolecules for diagnostic use in MRI.

The macromolecules of the present invention can also be linked tochelates of radioactive metal ions for use in nuclear medicine, orconjugated to iodinated molecules for use in all roentgenographicdiagnostic investigations.

The molecules may also be labelled with isotopes such as ¹³ C, ¹⁴ C, ²H, ³ H or ¹²⁵ I and used subsequently in biodistribution studies.Moreover, they may be used in the preparation of pharmaceutical productswhere controlled release of the active principle is required. Moreover,it is even possible to modify the external functional groups withsuitable hydrophobic groups to create a molecular structure that behavesas an inverse micelle, i.e. with a hydrophilic internal part and ahydrophobic surface.

Moreover such macromolecules are highly promising as carriers ofcatalysts, allowing a complete recovery of the same after the reaction.Finally, since the macromolecules of the present invention can beprepared to precise and definite dimensions, they are particularlyuseful as calibration standards for separation techniques based onmolecular shape, such as for example size-exclusion chromatography.

The compounds of the present invention are represented by the followinggeneral formula (I)

    A G.sub.1→p !r                                      (I),

where:

A is a central nucleus, or "core", deriving from a polyvalent organicmolecule which can be an aliphatic open chain, branched or not, residue,or an alicyclic, or a heterocyclic residue containing N, O and/or S, oran aromatic or a heteroaromatic residue and which is characterized bythe presence of r terminal residues to which the polyoxaalkyl chains ofthe first generation are attached,

r is an integer from 2 to 10 representing the multiplicity of the "core"A,

G₁→p represents the branched structure of the macromolecule comprising glevels of generations, from the first one (g₁) to the last one (g_(p))in which the total p number of said generations can range from 1 to 20and in which the different generations can contain the same repetitionunits or not, and in which:

a) each generation g, except for the last, comprises a number ofrepetition units, which are represented by residues of formula

    --B--M--

where:

B is preferably a polyoxyethylene or polyoxypropylene chain of formula:##STR3## in which n can range from 0 to 25 and is different or not fromgeneration to generation, provided that, in at least one of thegenerations of the macromolecule, n is different from 0,

M represents a branching point which derives from a polyvalent aliphaticresidue comprising:

a single functional group such as OH, NH₂, SH, COOH, or a derivativethereof, able to link with the terminal group of chain B,

m reactive residues for the linking of the polyoxaalkyl chains of thenext generation, being

m an integer ranging from 2 to 5, representing the branchingmultiplicity introduced by M and being m different or not fromgeneration to generation, and

being the total number of repetition units --B--M-- in each generationlevel g equal to the sum of all the branching multiplicities m of thepreceding generation g₋₁ ;

b) the last generation gp comprises residues of formula:

    --B.sub.p --M.sub.p  T!.sub.mp

where B_(p), M_(p), m_(p) are defined analogously to B, M, and m, withthe difference that all the M_(p) reactive residues of M_(p) areconnected to groups T in which

T is a terminal group that can be either H or one of the followingresidues: halo, hydroxyl, amino, thiol, --O-tosyl, --O-mesyl,--O-tresyl, --O-brosyl and similar groups, trifluoromethanesulfonyl,aldehydo, carboxy, amido group, such a terminal group T being free,either dissociated or undissociated, or protected by suitable protectivegroups such as for example, pyranyl, phthalimido, acetyl, cyclicorthoester group etc. and

being the total number of the terminal groups r equal to the sum of allthe branching multiplicities m of the last generation g_(p), and withthe further condition that

M_(p) can also be a single bond, in which case m_(p) is equal to 1(i.e., there is no branching) and as a consequence the last generationg_(p) comprises residues of formula: --B_(p) --T

where B_(p) and T are as above defined;

c) in case p=1, that is when the macromolecule contains only onegeneration, g_(p) corresponds to g₁, i.e. represents the residue:

    --B.sub.1 --M.sub.1  T!.sub.m1

where B₁, M₁, m₁ and T are defined analogously to B_(p), M_(p), m_(p)and T.

As a consequence, in this case the macromolecule is represented by thefollowing formula

    A g.sub.1 !.sub.r, i.e.

    A B.sub.1 --M.sub.1  T!.sub.m1 !.sub.r

in which A, B₁, M₁, T, m₁ and r are defined as above.

Compounds of general formula (I) also comprise those ones which arelabelled with isotopes such as ¹³ C, ¹⁴ C, ² H, ³ H, and ¹²⁵ I.

For seek of clarity a schematic representation of the structure of themacromolecules of the present invention is sequentially developedaccording to the following series of formulae:

    A G.sub.1→p !.sub.r                                 (I),

where:

G₁→p represents B₁ --M₁ G₂→p !m₁, in which B₁ --M₁ is g₁ and

G₂→p represents B₂ --M₂ G₃→p !m₂, in which B₂ --M₂ is g₂ and

so on until the last generation is reached in which

G_(p) represents B_(p) -M_(p) T!_(mp),

where the symbols used are as above defined.

The afore-mentioned development can be illustrated in complete form bythe following expanded general formula (II)

    A B.sub.1 --M.sub.1  B.sub.2 --M.sub.2  →→→ B.sub.p --M.sub.p  T!.sub.mp !→→→!.sub.m2 !.sub.m1 !.sub.r (II)

Compounds of the present invention which are particularly preferred arethose in which r ranges from 2 to 6, preferably from 2 to 4 and in whichthe "core" A is a neopentyl residue of formula ##STR4##

Equally preferred are those in which B is a polyoxyethylene chain offormula ##STR5## in which n is an integer from 0 to 25, preferably from0 to 15.

Also preferred are those in which M is a bi- or trifunctional branchingpoint represented by a residue of formula: ##STR6## in which q is aninteger from 0 to 4, preferably from 1 to 2.

Preferred macromolecular compounds are those in which the total numberof generations ranges from 1 to 20, preferably from 1 to 15.

As an example of the invention one of the preferred classes of compoundsis represented by those having the following general formula (III)##STR7## in which: n is an integer from 0 to 20, preferably from 0 to15, and with the condition that n is different from 0 in at least onegeneration,

g'₁ is the first generation having a branching multiplicity of 3,

L represents T, or the sequence of successive generations from g'₂ tog'_(p) in which each g', apart from g'_(p), is defined analogously tog'₁ and can have the same meaning or not whereas g'_(p) corresponds tog'₁ -T and T is as above defined; moreover the number of generations gcan be as high as 20, preferably 15.

The present invention is illustrated particularly through thepreparation of branched macromolecules having a neopentyl "core" fromwhich four polyoxyethylene chains depart. The branching is obtainedthrough the introduction of a residue of pentaerythritol on the terminalresidue of the polyoxyethylene chains. The synthesis of the compounds ofthe present invention can preferably be performed by two independentsynthetic processes:

a) lengthening of the polyoxyethylene chain,

b) branching.

The order of these synthetic pathways can be modulated at will, inparticular with regard to the type of compound and reaction conditionsemployed. It is possible to decide to begin with the central nucleus andadd successively the polyoxaalkyl chains of the first generation, thebranching points, the polyoxaalkyl chains of the second generation, thenew branching points and so on until the desired number of generationshas been reached.

Alternatively, it is equally possible to prepare already branchedpolyoxaalkyl chains and then to attach these to either the centralnucleus or to a previously formed generation.

Obviously, just as it is possible to utilize one or the other of the twosynthetic processes, it is also possible to follow in part the firstprocess and in part the second one according to the synthetic problem toovercome. The reactive functions not involved in a specific reaction areprotected with suitable protective groups according to methods wellknown in chemical syntheses. A consequence of this is that also theprocess of preparation of these macromolecular compounds forms anembodiment of the present invention.

An illustrative view of the preferred synthetic pathways is given in theexperimental part below.

Obviously, the experimental part only has the aim of exemplifying theinvention more completely. Consequently, it is not absolutely limitingof the invention itself and any possible change that can be produced inthe described examples is immediately evident to the expert technician.

EXAMPLE 1

Preparation of chlorooxyethylene chains with hydroxyl functionsprotected by dihydropyran

3,4-Dihydro-2H-pyran (0.6 mol) was slowly added dropwise into thedesired chloroalcohol (0.5 mol) of Table II under magnetic stirring. Thereaction temperature reached 100°-150° C. After allowing to cool to roomtemperature, the mixture was stirred for 2 h. The mixture was distilledunder high vacuum to obtain the desired product as a colourless oil. Bythis synthetic pathway the following products were obtained:

AI 2-(3-chloroethoxy)oxane (C₇ H₁₃ ClO₂)

AII 2-(3-oxa-5-chloropentyloxy)oxane (C₉ H₁₇ ClO₃)

AIII 2-(3,6-dioxa-8-chlorooctyloxy)oxane (C₁₁ H₂₁ ClO₄)

The reaction yields and starting materials are summarised in Table II.Table III reports the analytical characterizations.

                  TABLE II                                                        ______________________________________                                        Synthesis of protected oxyethylene chains                                                                  Reaction                                         Product  Starting chloroalcohol                                                                            yield                                            ______________________________________                                        AI       ClCH.sub.2 CH.sub.2 OH                                                                            85%                                              AII      ClCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                         91%                                              AIII     ClCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                         80%                                              ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Analytical characterization.sup.a                                             Pro-                                                                          duct b.p. (pressure)                                                                           Elemental analysis                                           ______________________________________                                        AI   100° C. (2676 Pa)                                                                  Calculated for C.sub.7 H.sub.13 ClO.sub.2 :                                                   C 51.11; H 7.96                                               found:          C 51.21; H 7.74                              AII  85° C. (60 Pa)                                                                     Calculated for C.sub.9 H.sub.17 ClO.sub.3 :                                                   C 51.80; H 8.21                                               found:          C 51.64; H 8.16                              AIII 125° C. (60 Pa)                                                                    Calculated for C.sub.11 H.sub.21 ClO.sub.4 :                                                  C 51.80; H 8.40                                               found:          C 51.49; H 8.44                              ______________________________________                                    

¹ H-NMR and ¹³ C-NMR spectra of the described products are in agreementwith the proposed structures.

Similar results were obtained when, in place of the above-mentionedmonofunctional chloroalcohols, the bifunctional chloroalcohols, ClCH₂--CH(CH₂ OH)₂ and ClCH₂ --CH₂ --O--CH₂ -- CH(CH₂ OH)₂, were protected bypyranyl groups.

EXAMPLE 2

Alkylation By Phase Transfer Catalysis of Neopentyl "Core" MoleculesWith Protected Oxyethylene Chains

The starting tetraalcohol (0.0156 mol) (Table IV) was dissolved in19.06M NaOH (0.624 mol). The reaction mixture was than warmed to 65° C.under nitrogen and mechanically stirred. Tetrabutylammonium bromide(0.0062 mol) and the desired chlorooxyethylenepyranyl derivative (0.0936mol) of Table IV, obtained according to the method of Example 1, werethen added to this solution. The reaction mixture was incubated at 65°C. for 48 h. After this time a freshly prepared 19.06M NaOH solution(0.312 mol), the chlorooxyethylenepyranyl derivative (0.062 mol),tetraoctylammoniumbromide (0.0062 mol) and Nal (0.0036 mol) were added.The reaction mixture was stirred for an additional 66 h at 65° C.Tetraethylammonium hydroxyde solution (10 mL; 10% w/w in water) was thenadded and the mixture stirred for 48 h at 80° C. Finally the reactionwas cooled to room temperature, diluted with H₂ O and the productextracted several times with diethylether. The organic layers werecombined and dried over Na₂ SO₄, filtered and concentrated under reducedpressure. The crude product thus obtained was subjected to fractionaldistillation and then chromatographed on a silica gel column (flashchromatography, eluent AcOEt). By this synthetic pathway the followingwere obtained:

BI 1,4,7,11,14,17-hexaoxa-1,17-bis(oxan-2-yl)-9,9-bis2,5,8-trioxa-8-oxan-2-yl)octyl!heptadecane (C₄₁ H₇₆ O₁₆);

BII,III 1,4,7,10,14,17,20,23-octaoxa-1,23-bis(oxan-2-yl)-12,12-bis2,5,8,11-tetraoxa-11-(oxan-2-yl)-undecyl!tricosane (C₄₉ H₉₂ O₂₀);

BIV,V 1,4,7,10,13,17,20,23,26,29-decaoxa-1,29-bis(oxan-2-yl)-15,15-bis2,5,8,11,14-pentaoxa-14-(oxan-2-yl)tetradecyl!nonacosane (C₅₇ H₁₀₈ O₂₄).

The reaction yields and starting materials are summarised in Table IV.Table V reports the analytical characterizations.

                                      TABLE IV                                    __________________________________________________________________________    Alkylation reactions by phase transfer catalysis                              Product                                                                           Starting chlorooxyethylenepyran compound                                                           Starting tetraalcohol                                                                           Reaction yield                     __________________________________________________________________________    BI                                                                                 ##STR8##            C(CH.sub.2 OH).sub.4                                                                            54%                                BII.sup.a                                                                          ##STR9##            C(CH.sub.2 OH).sub.4                                                                            20%                                BIII.sup.a                                                                         ##STR10##                                                                                          ##STR11##        50%                                BIV.sup.b                                                                          ##STR12##                                                                                          ##STR13##        42%                                BV.sup.b                                                                           ##STR14##                                                                                          ##STR15##        39%                                __________________________________________________________________________     .sup.a BII and BIII are the same product but synthetized from different       starting materials.                                                           .sup.b BIV and BV are the same product but synthetized from different         starting materials.                                                      

                  TABLE V                                                         ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                             Elemental analysis                                                      ______________________________________                                        BI    Calculated for C.sub.41 H.sub.76 O.sub.16 :                                                          C 59.69; H 9.29                                        found:                 C 59.60; H 9.28                                  BII   Calculated for C.sub.49 H.sub.92 O.sub.20 · 0.7 mol                  H.sub.2 O:             C 58.08; H 9.23                                        found:                 C 58.16; H 9.30                                  BIII  Calculated for C.sub.49 H.sub.92 O.sub.20 :                                                          C 58.78; H 9.26                                        found:                 C 58.71; H 9.30                                  BIV   Calculated for C.sub.57 H.sub.108 O.sub.24 · 0,5 mol                 H.sub.2 O:             C 57.66; H 9.25                                        found:                 C 57.29; H 9.26                                  BV    Calculated for C.sub.57 H.sub.108 O.sub.24 · 0,6 mol                 H.sub.2 O:             C 57.66; H 9.25                                        found:                 C 57.49; H 9.37                                  ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 3

Deprotection Reaction of the Pyranyl Derivatives

The desired tetraoxyethylenepyranyl derivative (0.0024 mol) (Table VI),obtained according to the method of Example 2, was dissolved in amixture of CH₂ Cl₂ /MeOH 1/1 (v/v) (20 mL). 37% HCl (0.5÷0.8 mL) wasadded and the reaction mixture was stirred for 7 h at room temperature.

Subsequently, NaHCO₃ was added to neutral pH, the inorganic salts werefiltered off and the organic layer dried over Na₂ SO₄. The solvent wasthen removed under vacuum. The crude product was chromatographed on asilica gel column (eluent CH₂ Cl₂ /MeOH=85/15 (v/v)). By this syntheticpathway the following compounds were obtained:

CI3,6,10,13-tetraoxa-8,8-bis-(2,5-dioxa-7-hydroxyheptyl)pentadecan-1,15-diol(C₂₁ H₄₄ O₁₂);

CII3,6,10,13,16,19-hexaoxa-11,11-bis(2,5,8-trioxa-10-hydroxydecyl)enicosan-1,21-diol(C₂₉ H₆₀ O₁₆);

CIII14,14-bis(2,5,8,11-tetraoxa-13-hydroxydecyl)-3,6,9,12,16,19,22,25-octaoxaheptacosan-1,27-diol(C₃₇ H₇₆ O₂₀)

The reaction yields and starting materials are summarised in Table VI.Table VII reports the analytical characterizations.

                                      TABLE VI                                    __________________________________________________________________________    Deprotection reactions                                                        Product                                                                           Starting tetraoxyethylenepyranyl                                                                            Reaction yield                              __________________________________________________________________________    CI                                                                                 ##STR16##                    92%                                         CII                                                                                ##STR17##                    90%                                         CIII                                                                               ##STR18##                    93%                                         __________________________________________________________________________

                  TABLE VII                                                       ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental analysis                                                     ______________________________________                                        CI     Calculated for C.sub.21 H.sub.44 O.sub.12 · 2,25 mol                 H.sub.2 O:            C 47.67; H 9.24                                         found:                C 47.33; H 9.15                                  CII    Calculated for C.sub.29 H.sub.60 O.sub.16 · 1 mol H.sub.2            O:                    C 51.01; H 9.15                                         found:                C 50.76; H 9.31                                  CIII   Calculated for C.sub.37 H.sub.76 O.sub.20 · 1.25 mol                 H.sub.2 O:            C 51.46; H 9.10                                         found:                C 51.36; H 9.24                                  ______________________________________                                         .sup.a1 H-NMR and .sup.1 3CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 4

Tosylation of the Tetraoxyethylenealcohols

The desired tetraoxyethylenealcohol (0.0102 mol) (Table VIII), obtainedaccording to the method of Example 3, was dissolved in CH₂ Cl₂.Triethylamine (0.123 mol) was added and the solution cooled to -5° C. Asolution of p-toluenesulfonyl chloride (0.0445 mol) in CH₂ Cl₂ was thenadded dropwise. The mixture was stirred for an additional 1 h at 0° C.and then left at room temperature for 24 h. The mixture was washed withwater and the organic layer separated and dried over Na₂ SO₄. Thesolvent was then removed under vacuum. The crude product was purified bychromatography on a silica gel column (eluent CHCl₃ /AcOEt 1/1 (v/v)).By this synthetic pathway the following compounds were obtained:

DI 1,4,7,11,14,17-hexaoxa-1,17-bis(p-toluensulfonyl)-9,9-bis2,5,8-trioxa-8-(p-toluenesulfonyl)octyl!heptadecane (C₄₉ H₆₈ O₂₀ S₄)

DII 1,4,7,10,14,17,20,23-octaoxa-1,23-bis(p-toluenesulfonyl)-12,12-bis2,5,8,11-tetraoxa-11-(p-toluenesulfonyl)undecil!tricosane (C₅₇ H₈₄ O₂₄S₄)

DIII 15,15-bis2,5,8,11,14-pentaoxa-14-(p-toluenesulfonyl)tetradecyl!-1,29-bis(p-toluensulfonyl)-1,4,7,10,13,17,20,23,26,29-decaosanonacosane(C₆₅ H₁₀₀ O₂₈ S₄)

The reaction yields and starting materials are summarised in Table VIII.Table IX reports the analytical characterizations.

                  TABLE VIII                                                      ______________________________________                                        Tosylation reactions of the tetraoxyethylenealcohols                          Pro-                            Reaction                                      duct Starting tetraoxyethylenealcohol                                                                         yield                                         ______________________________________                                        DI   C(CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OH).sub.4                                               75%                                                CI                                                                       DII  C(CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2           OH).sub.4                  65%                                                CII                                                                      DIII C(CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2           OCH.sub.2 CH.sub.2 OH).sub.4                                                                             60%                                                CIII                                                                     ______________________________________                                    

                  TABLE IX                                                        ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                             Elemental analysis                                                      ______________________________________                                        DI    Calculated for C.sub.49 H.sub.68 O.sub.20 S.sub.4 ·                                      C 58.84; H 6.24; S 11.52                                  mol H.sub.2 O:                                                                found:              C 52.46; H 6.26; S 11.40                            DII   Calculated for C.sub.57 H.sub.84 O.sub.24 S.sub.4 :                                               C 53.42; H 6.61; S 10                                     found:              C 53.65; H 7.00; S 10.14                            DIII  Calculated for C.sub.65 H.sub.100 O.sub.28 S.sub.4 :                                              C 53. 55; H 6.91; S 8.80                                  found:              C 53.38; H 6.93; S 8.68                             ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

In another tosylation experiment at kg scale, the reaction yield for DIwas improved to 90% by inverting the addition order of the reagents andby keeping the reaction temperature at 0° C.

EXAMPLE 5

Reaction of the Tosyl Derivatives With Potassium Phthalimide

thee desired tetraoxyethylenetosyl derivative (0.0018 mol) (Table X),obtained according to the method of Example 4, was dissolved in DMF.Potassium phthalimide (0.0072 mol) suspended in DMF was then added tothe solution. After 7 h at 140° C. the reaction mixture was cooled toroom temperature. The DMF was then removed under vacuum and H₂ O addedto the residue. The reaction mixture was taken up and extracted with CH₂Cl₂. The organic layer was dried over Na₂ SC)₄, filtered and the solventremoved under vacuum. The crude product was chromatographed on a silicagel column (flash chromatography; eluent AcOEt/CHCl₃ =7/3 (v/v)). Bythis synthetic pathway the following compounds were obtained:

EI 3,6,10,13-tetraoxa-1,15-bis(phthalimido)-8,8-bis2,5-dioxa-7-(phthalimido)heptyl! pentadecane (C₅₃ H₅₆ N₄ O₁₆)

EII 3,6,9,13,16,19-hexaoxa-1,21-bis(phthalimido)-11,11-bis2,5,8-trioxa-10-(phthalimido) decyl!enicosane (C₆₁ H₇₂ N₄ O₂₀)

The reaction yields and starting materials are summarised in Table X.Table XI reports the analytical characterizations.

                                      TABLE X                                     __________________________________________________________________________    Reaction with potassium phthalimide                                                                              Reaction                                   Product                                                                           Starting tetraoxyethylenetosyl derivative                                                                    yield                                      __________________________________________________________________________    EI                                                                                 ##STR19##                     85%                                         EII                                                                               ##STR20##                     65%                                        __________________________________________________________________________

                  TABLE XI                                                        ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental analysis                                                     ______________________________________                                        EI     Calculated for C.sub.53 H.sub.56 N.sub.4 O.sub.16                                               C 62.20; H 5.52; N 5.47                                     1 mol H.sub.2 O:                                                              found:            C 62.55; H 5.71; N 5.44                              EII    Calculated for C.sub.61 H.sub.72 N.sub.4 O.sub.20 :                                             C 62.02; H 6.14; N 4.74                                     found:            C 61.65; H 6.22; N 4.6                               ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 6

Conversion of the Phthalimido Derivative into the CorrespondingTetraoxyethyleneamino Derivative

The tetraoxyethylenephthalimido derivative EI (0.00199 mol) (Table XII),obtained according to the method of Example 5, was suspended in absoluteethanol. A solution of hydrazine (0.0119 mol) in absolute ethanol wasthen added otherwise. The reaction mixture was refluxed for 7 h and thencooled to room temperature. A precipitate was formed and filtered andthe solvent removed under vacuum to give the final product. By thissynthetic pathway the following compound was obtained:

FI3,6,10,13-tetraoxa-8,8-bis(2,5-dioxa-7-aminoheptyl)pentadecan-1,15-diamine(C₂₁ H₄₈ N₄ O₈)

The reaction yield and the starting material are summarised in TableXII. Table XIII reports the analytical characterizations.

                  TABLE XII                                                       ______________________________________                                        Conversion of the phthalimido derivative                                      into the tetraoxyethyleneamino derivative                                           Starting                   Re-                                                tetraoxyethylenephthalimido                                                                              action                                       Product                                                                             derivative                 yield                                        ______________________________________                                        FI                                                                                   ##STR21##                 70%                                          ______________________________________                                    

                  TABLE XIII                                                      ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental analysis                                                     ______________________________________                                        FI     Calculated for C.sub.21 H.sub.48 N.sub.4 O.sub.8                                                C 46.96; H 10.14; N 10.43                                   3 mol H.sub.2 O:                                                              found:            C 46.83; H 9.96; N 10.03                             ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 7

Conversion of the Tosyl Derivative into the CorrespondingTetraoxyethylenebromide Derivative

The tetraoxyethylenetosyl derivative DI (0.00325 mol) (Table XIV),obtained according to the method of Example 4, was dissolved inN,N-dimethylacetamide. NaBr (0.026 mol) was added and the reactionmixture stirred for 1 h at 150° C. The mixture was then cooled to roomtemperature and the solvent removed under vacuum. The residue was takenup into water and extracted with AcOEt. The organic layer was dried overNa₂ SO₄, filtered and the solvent removed under vacuum. The crudeproduct was purified by chromatography on a silica gel column (eluentAcOEt/CHCl₃ 1/1 (v/v)). By this synthetic pathway the following compoundwas obtained:

GI3,6,10,13-tetraoxa-8,8-bis(2,5-dioxa-7-bromoheptyl)pentadecan-1,15-dibromide(C₂₁ H₄₀ O₈ Br₄)

The reaction yield and starting material are summarised in Table XIV.Table XV reports the analytical characterization.

                  TABLE XIV                                                       ______________________________________                                        Conversion of the tosylderivative                                             into the tetraoxyethylenebromide derivative                                         Starting                   Re-                                                tetraoxyethylenetosyl      action                                       Product                                                                             derivative                 yield                                        ______________________________________                                        GI                                                                                   ##STR22##                 60%                                          ______________________________________                                    

                  TABLE XV                                                        ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental Analysis                                                     ______________________________________                                        GI     Calculated for C.sub.21 H.sub.40 O.sub.8 Br.sub.4                                              C 34.08; H 5.45; Br 43.18                                    3 mol H.sub.2 O:                                                              found            C 34.20; H 5.47; Br 43.04                             ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 8

Branching of the Oxyethylene Chains by Reaction With Compounds HavingFurther Functional Groups For Subsequent Alkylation (Example ofIntroduction of a Branching Point With Multiplicity=3)

4-(Hydroxymethyl)-2,6,7-trioxabicyclo 2.2.2!octane (0.00452 mol),prepared according to the method described by Padias et al. (Ref. 5),was dissolved in diethyleneglycol dimethylether (15 mL) and then addeddropwise at 0° C. to a solution containing a stoichometric quantity ofpotassium hydride. The reaction mixture was stirred for 1 h at 0° C. andthen for 3 h at room temperature. The desired tetraoxyethylenetosylderivative (0.001808 mol) (Table XVI), obtained according to the methodof Example 4, and dissolved in diethyleneglycol dimethylether (25 mL)was then added dropwise to the solution. The reaction mixture was thenstirred at 120° C. for 14 h. After cooling to room temperature, thesolvent was removed under vacuum and the mixture taken up with water andextracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄,filtered and the solvent removed under vacuum. The crude product waspurified by chromatography on a silica gel column (eluent AcOEt). Thefractions containing the product were combined and the solvent removedunder vacuum. The residue was dissolved in MeOH and then 37% HCl wasadded. The mixture was refluxed and the MeOH distilled off very slowlyover a period of 2 h. The mixture was cooled to room temperature and theremaining MeOH removed under vacuum. The product was then obtained as acolourless oil. By this synthetic pathway the following compounds wereobtained:

HI 4,7,10,14,17,20-hexaoxa-2,2,22,22-tetra(hydroxymethyl)-12,12-bis2,5,8-trioxa-10,10-bis(hydroxymethyl)-11-hydroxyundecyl!tricosan-1,23-diol(C₄₁ H₈₄ O₂₄)

HII 18,18-bis2,5,8,11,14-pentaoxa-16,16-bis(hydroxymethyl)-17-hydroxyheptadecyl!-2,2,34,34-tetra(hydroxymethyl)-4,7,10,13,16,20,23,26,29,32-decaoxapentatriacontan-1,35-diol(C₅₇ H₁₁₆ O₃₂)

The reaction yield and starting material are summarised in Table XVI.Table XVII reports the analytical characterization.

                                      TABLE XVI                                   __________________________________________________________________________    Branching reactions                                                               Branching                                Reaction                         Product                                                                           junction                                                                            Tetraoxyethylenetosyl derivative   yield                            __________________________________________________________________________    HI  C(CH.sub.2 OH).sub.4                                                                 ##STR23##                         35%                               HII                                                                              C(CH.sub.2 OH).sub.4                                                                 ##STR24##                         29%                              __________________________________________________________________________

                  TABLE XVII                                                      ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                             Elemental analysis                                                      ______________________________________                                        HI    Calculated for C.sub.41 H.sub.84 O24 · 2.5 mol H.sub.2                                      C 50.38; H 8.87                                        found:                 C 50.25; H 9.02                                  HII   Calculated for C.sub.57 H.sub.116 O.sub.32 · 2.5 mol                 H.sub.2 O:             C 50.29; H 8.98                                        found:                 C 50.37; H 8.98                                  ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 9

Tosylation Reaction of Branched Alcohols Derivatives

The branched alcohol HI (0.00208 mol) (Table XVIII), obtained accordingto the method of Example 8, was dissolved in pyridine (40 mL) and thesolution cooled to -5° C. A solution of p-toluenesulfonyl chloride(0.00583 mol) in pyridine (50 mL) was then added dropwise. The mixturewas stirred for 1 h at 0° C. and then left at room temperature for 4days. Water was added and the mixture extracted with CHCl3. The organiclayer was dried over Na₂ SO₄ and then the solvent was removed undervacuum. The crude product was purified by chromatography on a silica gelcolumn (eluent AcOEt/CHCl₃ 1/1 (v/v)). By this synthetic pathway thefollowing compound was obtained:

LI 1,23-di(p-toluenesulfonyloxy)-12,12-bis11-(p-toluenesulfonyloxy)-10,10-bis(p-toluenesulfonyloxymethyl)-2,5,8-trioxaundecyl!-2,2,22,22-tetra(p-toluenesulfonyloxymethyl)-4,7,10,14,17,20-hexaoxatricosane(C₁₂₅ H₁₅₆ O₄₈ S₁₂)

The reaction yield and starting material are summarised in Table XVIII.Table XIX reports the analytical characterization.

                  TABLE XVIII                                                     ______________________________________                                        Tosylation of the branched alcohol                                                                            Reaction                                      Product                                                                              Starting branched alcohol                                                                              yield                                         ______________________________________                                        LI     C CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2                    C(CH.sub.2 OH).sub.3 !.sub.4                                                                           50%                                                  HI                                                                     ______________________________________                                    

                  TABLE XIX                                                       ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental analysis                                                     ______________________________________                                        LI     Calculated for C.sub.125 H.sub.156 O.sub.48 S.sub.12                                            C 53.40; H 5.59; S 13.69                                    1 mol H.sub.2 O:                                                              found:            C 53.78; H 5.86; S 13.35                             ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 10

Conversion of the Branched Tosyl Derivatives into the CorrespondingBromo Derivatives

The tosyl derivative LI (0.00051 mol) (Table XX), obtained according tothe method of Example 9, was dissolved in N,N-dimethylacetamide (50 mL).NaBr (0.01224 mol) was added and the reaction mixture stirred for 1 h at150° C. The temperature was then cooled to room temperature and thesolvent removed under vacuum. The residue was taken up with water andextracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and thesolvent removed under vacuum.

The crude product was purified by chromatography on a silica gel column(eluent AcOEt/CHCl3 1/2 (v/v)). By this synthetic pathway the followingcompound was obtained:

MI 1,23-dibromo-12,12-bis11-bromo-10,10-bis(dibromomethyl)-2,5,8-trioxaundecyl!-2,2,22,22-tetrabromomethyl-4,7,10,14,17,20-exaoxatricosane(C₄₁ H₇₂ O₁₂ Br₁₂)

The reaction yield and starting material are summarised in Table XX.Table XXI reports the analytical characterization.

                                      TABLE XX                                    __________________________________________________________________________    Conversion into bromo derivative                                                                                    Reaction                                Product                                                                           Branched tosyl derivation         yield                                   __________________________________________________________________________    MI                                                                                 ##STR25##                        67%                                     __________________________________________________________________________

                  TABLE XXI                                                       ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental analysis                                                     ______________________________________                                        MI     Calculated for C.sub.41 H.sub.72 O.sub.12 Br.sub.12 :                                           C 28,7; H 4.23; Br 55.88                                    found:            C 28,93; H 4.33; Br 55.65                            ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

EXAMPLE 11

Introduction of Polyoxyethylene Chains on Molecules With BranchedAlcohol Terminal Groups

The branched alcohol HI (0.00104 mol) (Table XXII), obtained accordingto the method of Example 8, was dissolved in 19.06M NaOH (0.125 mol)under nitrogen. The reaction mixture was warmed up to 65° C. undermechanical stirring. Tetrabutylammonium bromide (0.00042 mol) and thechlorooxyethylenepyranyl derivative (0.00187 mol) were then added. Thereaction mixture was incubated at 65° C. for 72 h.

Freshly prepared 19.06M NaOH solution (0.125 mol), thechlorooxyethylenepyranyl derivative (0.0125 mol), tetraoctylammoniumbromide (0.000104 mol) and NaI (0.00005 mol) were added and the reactionwas stirred for 72 h at 65° C. Tetraethylammonium hydroxide solution (5mL; 10% w/w in water) was added and the mixture stirred for 96 h at 80°C. Finally the reaction was cooled to room temperature, diluted withwater and extracted with CHCl₃. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude productwas chromatographed on a silica gel column. The by-products were elutedwith AcOEt and the compound of interest was eluted with a mixture ofAcOEt/Acetone 7/3 (v/v). By this synthetic pathway the followingcompound was obtained:

NI 1,35-di(oxan-2-yl-oxy)-18,18-bis17-(oxan-2-yl-oxy)-10,10-bis(7-(oxan-2-yl-oxy)-2,5-dioxaheptyl)-2,5,8,12,15-pentaoxaheptadecyl!-8,8,28,28-tetra(7-oxan-2-yl-oxy)-2,5-dioxaheptyl!3,6,10,13,16,20,23,26,30,33-decaoxapentatricontane(C₁₄₉ H₂₇₆ O₆₀)

The reaction yield and starting material are summarised in Table XXII.Table XXIII reports the analytical characterization.

                                      TABLE XXII                                  __________________________________________________________________________    Introduction of protected oxyethylene chain                                                                            Reaction                             Product                                                                           Starting alcohol     Pyranyl derivative                                                                            yield                                __________________________________________________________________________    NI                                                                                 ##STR26##                                                                                          ##STR27##      40%                                  __________________________________________________________________________

                  TABLE XXIII                                                     ______________________________________                                        Analytical characterization.sup.a                                             Product                                                                              Elemental analysis                                                     ______________________________________                                        NI     Calculated for C.sub.149 H.sub.276 O.sub.60 ·                                          C 58.94; H 9.19; O 31.87                                    0,5 mol H.sub.2 O:                                                            found:            C 58.57; H 9.32; O 32.14                             ______________________________________                                         .sup.a1 H-NMR and .sup.13 CNMR spectra of the described products are in       agreement with the proposed structures.                                  

The same product was also obtained with a similar synthetic procedureusing only tetrabutylammonium hydrogen sulfate as catalyst. Followingsuch a procedure, the reaction yield was improved to 55%. The reactionyield for the introduction of twelve oxyethylene chains was surprisinglyhigh being at least equal or even superior to those observed for theintroduction of four oxyethylene chains as described in Example 2. Thisunexpected feature suggests that these compounds play a role in thephase-transfer catalysis.

Similar results were obtained when the described reaction was carriedout on branched molecules with multiplicity=2, or whenmonochlorodipyranyl derivatives such as those described in Example 1were utilized as lengthening units.

EXAMPLE 12

Introduction of a Further Branching Point (Multiplicity=3)

a) The second generation was obtained according to the method describedin Example 8 by reacting the dodecatosyl derivative LI, obtainedaccording to the method described in Example 9, with a stoichometricquantity of the potassium salt of 4-(hydroxymethyl)-2,6,7-trioxabicyclo2.2.2!octane. ##STR28## Yield: 19%.

¹ H-NMR, ¹³ C-NMR and mass spectra of all the products described are inagreement with the proposed structure. The same product can besynthesized by starting from the dodecabromo derivative (MI), obtainedusing the method described in Example 10, by using the same syntheticapproach of this example.

b) The compound NI, obtained according to the method described inExample 11, is converted first into the alcohol (QI) and then into thecorresponding tosyl derivative (RI) according to the methods describedin Examples 3 and 4. Finally, the corresponding second generationderivative (SI) is obtained by introducing a pentaerythritol unit oneach chain, according to the method described in Example 8. ##STR29##

The second generation product ##STR30## was also obtained, afterdeprotection of the corresponding orthoester, through the followingsynthetic pathways: ##STR31## Following similar procedures, products ofhigher generations were obtained.

EXAMPLE 13

Determination of Limiting Viscosity Numbers (Intrinsic Viscosity) and ofEquivalent Viscometric Radii

The viscosities of aqueous solutions of compounds of the presentinvention were determined by measuring the efflux times in an Ubbelohdecapillary viscometer controlled by an optical timing detector (AVS,Schott). During the experiments a constant temperature of 37°±0.005° C.was maintained. Density measurements were obtained by a Paar precisiondensimeter. The numerical evaluation of the limiting viscosity number(or intrinsic viscosity) was obtained from the following relationship##EQU1## where c corresponds to the concentration of the macromolecule,η is the viscosity of the solution, η_(o) is the viscosity of the puresolvent and k is an empirical parameter.

Numerical evaluations of equivalent viscometric radii (r) were obtainedby the following relationship ##EQU2## where M is the molar mass of themacromolecule and N_(A) is Avogadro's number.

Compounds HI, HII and QI have been compared with Tomalia's starburstpolyether dendrimers of first and second generation (C CH₂ OCH₂ C(CH₂OH)₃ !₄ and C CH₂ OCH₂ C(CH₂ OCH₂ C(CH₂ OH)₃)₃ !₄, respectively,described in Example 11 of U.S. Pat. No. 4,587,329) which do not possessoxyethylene units between the "core" and the first branching point andbetween the first and the second branching points, and which arecharacterized by a much more compact structure. Each of these compounds(except Tomalia's compound of second generation) has the same number ofsurface functional groups, i.e. 12 hydroxyl groups. The results aresummarized in Table XXIV.

                  TABLE XXIV                                                      ______________________________________                                        Limiting viscosity numbers (intrinsic viscosity) and equivalent               viscometric                                                                   radii of new polyoxyethylene branched macromolecules                                     Limiting viscosity number                                                                     Equivalent viscometric                             Product     η! mL · g.sup.-1 (at 37° C.)                                             radius (r) Å                                   ______________________________________                                        TOMALIA,   2.32 ± 0.06  6.08 ± 0.05                                     first generation                                                              HI         3.38 ± 0.07  8.01 ± 0.06                                     HII        4.04 ± 0.10  9.44 ± 0.08                                     QI         4.07 ± 0.04  10.92 ± 0.04                                    TOMALIA,   2.50 ± 0.03  9.30 ± 0.04                                     second generation                                                             ______________________________________                                    

The data clearly show that the introduction of oxyethylene units givesrise to compounds with radius values which can be even larger than thoseof higher generation described by Tomalia. With an extremely low, if notabsolutely negligeable, "dense-packing" effect there is, as aconsequence, the possibility to synthesize molecules up to whatevergeneration is desired or required for specific uses.

Analogous measurements carried out on macromolecules of successivegenerations further supported and these statements.

References

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3) Smith, P. B., Martin, S. J., Hall, M. J., and Tomalia, D. A. In J.Mitchell, Jr., (Ed.): Applied Polymer Analysis and Characterization,Hanser, Munchen/New York 1987, 357-385.

4) Tomalia, D. A., Dewald, J. R. (1986) U.S. Pat. No. 4,587,329.

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We claim:
 1. Dendrimeric macromolecules of the formula:

    A G.sub.1-p !.sub.r

having r number of structures G.sub.(1→p) in the dendrimer per structurewhere: A is a polyfunctional/polyvalent central nucleus, or core, whichis an aliphatic open chain, branched or unbranched, or an alicyclic, ora heterocyclic group containing N, O and/or S, or an aromatic or aheteroaromatic group and which contains terminal group to whichpolyoxaalkylene chains of a first generation shell are attached; r is aninteger from 2 to 10 representing the functionality of the core A and,as a consequence, also the total number of dendra, in whichG.sub.(1→p)is a single dendron linked to A, G.sub.(1→p) !_(r) represents thebranched structure of the macromolecule comprising p levels ofgeneration shells from the first one g.sub.(1) to the last oneg.sub.(p), in which the total number of said generation shells p canrange from 1 to 20 and in which the different generation shells maycontain the same repetition units, and in which: (a) each generationg.sub.(i), except for the last g.sub.(p), comprises repeating units,which are represented by a functional group of formula

    --B--M--

where: B is a polyoxaethylene or polyoxapropylene chain of formula:##STR32## in which n can range from 0 to 25 and may differ fromgeneration to generation and in which in at least one generation shellof the macromolecule, n is other than 0, M represents a branching pointwhich is a polyvalent aliphatic group comprising m reactive functionalgroups for the linking of the polyoxaalkylene chains of the nextgeneration shell, in which m in an integer ranging from 2 to 5 and m maydiffer from one generation shell to another; (b) the last generationshell g.sub.(p) comprises functional groups of formula:

    --B.sub.(p) --M.sub.(p)  T!.sub.m(p)

where B.sub.(p), M.sub.(p), m.sub.(p) defined analogously to B, M, andm, with all the m.sub.(p) reactive groups of M.sub.(p) connected togroups T, in which T is a terminal group that is either H or halo,hydroxyl, amino, thiol, --O-tosyl, --O-mesyl, --O-tresyl, --O-brosyl,trifluoromethanesulfonyl, aldehydo, carboxy or an amido group, saidterminal group T being free, either dissociated or undissociated, orprotected by a protective group, or M.sub.(p) is a single bond, nobranching exists and the last generation shell g.sub.(p) is formed bygroups of formula:

    --B.sub.(p) --T

where B.sub.(p), and T are as above defined, and (c) when p=1 themacromolecule contains only one generation shell, g.sub.(p) whichcorresponds to g.sub.(i) and has the formula:

    --B.sub.(1) --M.sub.(1)  T!m.sub.(1)

where B.sub.(1), M.sub.(1), m.sub.(1) and T are defined analogously toB.sub.(p), M.sub.(p), m.sub.(p) and T, said macromolecule optionallylabeled with an isotope.
 2. The macromolecule according to claim 1,whereina) said "core" A is a neopentyl group of formula: ##STR33## b)each generation, apart from the last one, comprises growth units offormula:

    --B'--M'--

wherein B' is a polyoxyethylene group of formula: ##STR34## wherein nranges from 0 to 15 and is the same or different from generation togeneration, and is different from 0 in at least one generation, M' is abranching point with a branching multiplicity of 2 or 3, of formula:##STR35## wherein q ranges from 1 to 2; c) the last generation is aresidue of formula:

    --B'.sub.p --M'.sub.p  T!.sub.2-3

wherein B'_(p), M'_(p) are defined as B', M' and T is definedhereinabove, or M'_(p) is a single bond, and when M'_(p) is a singlebond, the last generation corresponds to the group:

    --B'.sub.p --T

wherein B'_(p) and T are as defined above and wherein the total numberof generations ranges from 1 to
 15. 3. The macromolecule according toclaim 2, of formula (III) ##STR36## wherein: n ranges from 0 to 15, andn is different from 0 in at least one generation,g'₁ is the firstgeneration having a branching multiplicity of 3, L represents T orrepresents the sequence of successive generations from g'² to g'_(p) inwhich each g', except g'_(p), is defined as g'₁ and the same or adifferent meaning, whereas g'_(p) corresponds to g'¹ -T and the totalnumber of generations g is up to
 15. 4. The macromolecule according toclaim 1 of formula

    A B.sub.1 --M.sub.1  T!.sub.m1 !.sub.r.


5. The macromolecule according to claim 1 wherein in said formula

    A G.sub.1→p !.sub.r

G₁→p represents B₁ --M₁ G₂→p !_(m1), in which B₁ --M₁ is g₁ and G₂→prepresents B₂ --M₂ G₃→p !_(m2), in which B₂ --M₂ is g₂ until the lastgeneration is reached, in which G_(p) represents B_(p) --M_(p) T!_(mp).6. A dendrimeric type macromolecule which is a member selected from thegroup consisting ofa) BI:1,4,7,11,14,17-hexaoxa-1,17-bis(oxan-2-yl)-9,9-bis2,5,8-trioxa-8-oxan-2-yl)octyl!heptadecane; b) BII,III:1,4,7,10,14,17,20,23-octaoxa-1,23-bis(oxan-2-yl)-12,12-bis2,5,8,11-tetraoxa-11-(oxan-2-yl) undecyl!tricosane; c) BIV,V:1,4,7,10,13,17,20,23,26,29-decaoxa-1,29-bis(oxan-2-yl)-15,15-bis2,5,8,11,14-pentaoxa-14-(oxan-2-yl)tetradecyl!nonacosane; d) CI:3,6,10,13-tetraoxa-8,8-bis-(2,5-dioxa-7-hydroxyheptyl)pentadecan-1,15-diole) CII:3,6,10,13,16,19-hexaoxa-11,11-bis(2,5,8-trioxa-10-hydroxydecyl)enicosan-1,21-diol;f) CIII:14,14-bis(2,5,8,11-tetraoxa-13-hydroxydecyl)-3,6,9,12,16,19,22,25-octaoxaheptacosan-1,27-diol;g) GI:3,6,10,13-tetraoxa-8,8-bis(2,5-dioxa-7-bromoheptyl)pentadecan-1,15-dibromide;h) DI: 1,4,7,11,14,17-hexaoxa-1,17-bis(p-toluensulfonyl)-9,9-bis2,5,8-trioxa-8-(p-toluenesulfonyl)octyl!heptadecane; i) DII:1,4,7,10,14,17,20,23-octaoxa-1,23-bis(p-toluenesulfonyl)-12,12-bis2,5,8,11-tetraoxa-11-(p-toluenesulfonyl)undecil!tricosane; j) DIII:15,15-bis2,5,8,11,14-pentaoxa-14-(p-toluenesulfonyl)tetradecyl!-1,29-bis(p-toluensulfonyl)-1,4,7,10,13,17,20,23,26,29-decaosanonacosane;k) EI: 3,6,10,13-tetraoxa-1,15-bis(phthalimido)-8,8-bis2,5-dioxa-7-(phthalimido)heptyl! pentadecane; l) EII:3,6,9,13,16,19-hexaoxa-1,21-bis(phthalimido)-11,11-bis2,5,8-trioxa-10-(phthalimido) decyl!enicosane; m) FI:3,6,10,13-tetraoxa-8,8-bis(2,5-dioxa-7-aminoheptyl)pentadecan-1,15-diamine;n) HI: 4,7,10,14,17,20-hexaoxa-2,2,22,22-tetra(hydroxymethyl)-12,12-bis2,5,8-trioxa-10,10-bis(hydroxymethyl)-11-hydroxyundecyl!tricosan-1,23-diol;o) HII: 18,18-bis2,5,8,11,14-pentaoxa-16,16-bis(hydroxymethyl)-17-hydroxyheptadecyl!-2,2,34,34-tetra(hydroxymethyl)-4,7,10,13,16,20,23,26,29,32-decaoxapentatriacontan-1,35-diol;p) LI: 1,23-di(p-toluenesulfonyloxy)-12,12-bis11-(p-toluenesulfonyloxy)-10,10-bis(p-toluenesulfonyloxymethyl)-2,5,8-trioxaundecyl!-2,2,22,22-tetra(p-toluenesulfonyloxymethyl)-4,7,10,14,17,20-hexaoxatricosane;q) MI: 1,23-dibromo-12,12-bis11-bromo-10,10-bis(dibromomethyl)-2,5,8-trioxaundecyl!-2,2,22,22-tetrabromomethyl-4,7,10,14,17,20-exaoxatricosane;r) NI: 1,35-di(oxan-2-yl-oxy)-18,18-bis17-(oxan-2-yl-oxy)-10,10-bis(7-(oxan-2-yl-oxy)-2,5-dioxaheptyl)-2,5,8,12,15-pentaoxaheptadecyl!-8,8,28,28-tetra(7-oxan-2-yl-oxy)-2,5-dioxaheptyl!-3,6,10,13,16,20,23,26,30,33-decaoxapentatricontane.7. The macromolecule of claim 1 labeled with ¹³ C, ¹⁴ C, ² H, ³ H or,¹²⁵ I.
 8. A dendrimeric macromolecule consisting of a core, and at leasttwo cascade branched chains linked to said core, wherein said core is apolyvalent organic molecule and said branched chains comprise aplurality of repeating units, said units being the same or differentfrom one generation shell to another, each of said units consistingof(a) a polyoxaalkylene chain, and (b) a polyvalent branched aliphaticgroup having further branching points attached to it;said dendrimericmacromolecule having at the most 20 generation shells of said repeatingunits, the last of said generation shells having mono- or polyvalentfunctional terminal groups; and said polyoxaalkylene chain consists of noxyalkylene group wherein n is an integer ranging from 0 to 25 and isthe same or different from one generation shell to another and at leastin one of said generation shells is other than 0.